Update on paroxysmal nocturnal haemoglobinuria: on the long way to understand the principles of the disease

Abstract

The understanding of the clinical manifestations in paroxysmal nocturnal haemoglobinuria (PNH) has made great progress. The main symptoms of this disease such as abdominal pain, renal failure or pulmonary hypertension and even the basis of the dramatic thrombophilia can be related to intravascular haemolysis and liberation of free haemoglobin resulting in NO depletion. In addition, there has been a recent great progress in elucidating the pathophysiology of clonal expansion within PNH bone marrow. In the majority of patients with haemolytic PNH, there are additional mutations within genes beyond PIG-A and rather affecting growth and differentiation of clonal bone marrow cells. In contrast to the formerly proposed single mechanism hypotheses such as immune selection or intrinsic gain of clonal dominance, this appears to follow a pattern of a complex clonal hierarchy putatively integrating both earlier anticipated mechanisms. Treatment of PNH is mainly supportive. The only curative approach as allogeneic stem cell transplantation should only be applied to patients with complications such as secondary bone marrow aplasia or transformation into MDS or AML. Symptomatic haemolytic PNH will be treated with eculizumab, an inhibitor of the terminal complement cascade. Treatment with eculizumab can significantly prevent PNH-related symptoms including the abnormal thrombophilia. Recently, it was demonstrated that in contrast to untreated historic PNH patients, meanwhile a normal life expectancy is observed in eculizumab-treated patients. The recently approved vaccine against meningococci type B by the European Medical Agency (EMA) could probably further help to prevent meningococcal sepsis due to the induced complement deficiency by eculizumab.

Diagnostic screening of paroxysmal nocturnal hemoglobinuria: Prospective multicentric evaluation of the current medical indications

“…Of note, the percentage of PNH + patients that fulfilled the diagnostic criteria for BM aplasia (neutrophils <1,500 cells/uL) and severe BM aplasia (neutrophils <500 cells/uL) based on PB counts of GPI‐normal neutrophils, was >90% and 60% among PNH + cases with hemolytic disease; even more, >50% and 25% of PNH + patients who showed unexplained cytopenia/anemia and/or thrombosis had GPI‐normal neutrophil count in PB compatible with BM aplasia and severe BM aplasia, respectively, such rates being similar to those observed among AA and MDS patients. These results support the notion that an underlying BM defect exists in virtually all PNH + patient subgroups, although it might be masked by the parallel expansion of GPI‐deficient cells, particularly in patients presenting with classical PNH . In addition, our findings also suggest that in those PNH patients in whom the GPI‐defective hematopoiesis is not able to overcome the underlying BM defect, diagnosis of AA will most likely precede the detection of GPI‐deficient cells, whereas in the remaining PNH + cases, symptoms of hemolysis would predominate.…”

“…Despites PNH testing for MPN patients is currently not recommended, several cases have been recently described in which JAK‐2 , and CALR mutations, as well as BCR‐ABL gene rearrangements have been associated with PNH‐positivity , the precise frequency of PNH+ cases among MPN patients deserving further investigations. In contrast to what is described above for AA and MDS cases, presence of hemolysis or cytopenias does not appear to be sufficient indication for PNH testing in patients diagnosed of hematological and/or immunological disorder other than AA, MDS, and MPN, such as leukemia/lymphoma or autoimmune diseases .…”

“…Since delayed diagnosis has proven to increase morbidity, and even shorten the life expectancy of PNH patients , consensus recommendations have been made in recent years aiming at a more efficient diagnostic screening of the disease . Thus, general agreement exists on that flow cytometry testing for PNH should be requested in patients with: nonimmune (e.g., Coombs negative) hemolytic anemia; intravascular hemolysis associated with hemoglobinuria or unexplained hemolysis, in association with iron deficiency, abdominal pain, thrombosis, and/or cytopenia (e.g., neutropenia and/or thrombocytopenia); unexplained thrombosis particularly at unusual sites (e.g., Budd‐Chiari syndrome), and; BM failure syndrome, including AA, low‐grade MDS and idiopathic cytopenias of undetermined significance (ICUS) . Despite such consensus recommendations have been widely adopted and used, to the best of our knowledge no study has been reported so far in which the efficiency of PNH testing for each of these medical indications had been prospectively evaluated in parallel in multicenter vs. reference center settings.…”

“…Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder characterized by an acquired somatic mutation of the PIG-A gene which results in complete absence and/or lower expression of proteins which are anchored to the cell surface membrane through glycophosphatidylinositol (GPI) (1)(2)(3)(4)(5). In the last decades, multiparameter flow cytometry (FCM) has proven to be a robust method for the detection of GPI-deficient cells and the diagnostic screening of PNH (6)(7)(8).…”

“…In the last decades, multiparameter flow cytometry (FCM) has proven to be a robust method for the detection of GPI-deficient cells and the diagnostic screening of PNH (6)(7)(8). Despite this, diagnosis of PNH still remains a challenge due to the rarity of the disease (annual incidence rate of 0.5-1.3 cases/million individuals) (9,10), its heterogeneous clinical presentation (1)(2)(3)(4)(5) and the relatively limited awareness about its broad clinical spectrum which ranges from non-immune hemolytic anemia associated with hemoglobinuria and unexplained thrombosis, to smaller PNH clones in the context of a bone marrow (BM) failure syndrome -e.g. aplastic anemia (AA) or myelodysplastic syndrome (MDS)-, or even subclinical (i.e.…”